Congenital adrenal hyperplasia

Definitions & Key takeaways

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that affect the glandular cells in the adrenal cortex. This produces abnormal amounts of certain hormones, including cortisol, aldosterone, and androgen. These hormones are responsible for many essential functions in the body, including stress response, blood pressure, and kidney function.

There are several forms of CAH, each caused by a specific gene mutation. The most common form is called 21-hydroxylase deficiency, caused by a mutation in the CYP21A2 gene. 21-hydroxylase deficiency presents with masculinization in women and salt wasting, and hypoglycemia.

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Introduction0:00–0:30

With congenital adrenal hyperplasia, congenital means present from birth, adrenals refer to the two adrenal glands that sit above the kidney, and hyperplasia refers to increased cell proliferation which leads to tissue growth.
So congenital adrenal hyperplasia is a disease where there are enlarged adrenal glands that are present at birth, and the reason for the adrenal enlargement is that there’s a deficiency in an enzyme involved with steroid production.

Physiology0:30–5:40

Now, each adrenal gland one has an inner layer called the medulla and an outer layer called the cortex which is subdivided into three more layers, the zona glomerulosa, zona fasciculata, and the zona reticularis.
The outermost layer is the zona glomerulosa, and it’s full of cells that make the hormone aldosterone. The first step in aldosterone production is when an enzyme called cholesterol desmolase turns cholesterol into pregnenolone.
Pregnenolone is the precursor to all of the adrenal cortex hormones, sometimes called the steroid hormones. Next, pregnenolone is turned into progesterone by the enzyme 3 beta-hydroxysteroid dehydrogenase.
Then, progesterone is turned into 11 deoxycorticosterone by the enzyme 21 hydroxylase. 11 deoxycorticosterone then gets turned into corticosterone by the enzyme 11 beta-hydroxylase.
And finally, corticosterone is turned into aldosterone by the enzyme aldosterone synthase. Whew!
That’s like going through the washing machine twice. So the final result is aldosterone which is part of a hormone family called the renin-angiotensin-aldosterone system.
Aldosterone signals the kidney to reabsorb more Na+ into the blood and excrete more potassium. When Na+ is reabsorbed, water also moves into the blood, which increases blood volume and blood pressure.
The middle layer of the adrenal cortex is the zona fasciculata, and the cells there make the hormone cortisol. This process starts when pregnenolone and progesterone move into the zona fasciculata.
The enzyme 17 alpha -hydroxylase turns pregnenolone into 17 hydroxypregnenolone and turns progesterone into 17 hydroxyprogesterone.
17 hydroxypregnenolone is then turned into 17 hydroxyprogesterone by the enzyme 3 beta-hydroxysteroid dehydrogenase. Then, all of the 17 hydroxyprogesterone is turned into 11 deoxycortisol by the enzyme 21 hydroxylase.
11 deoxycortisol is finally turned into cortisol by the enzyme 11 beta-hydroxylase. Cortisol is needed in times of emotional and physical stress like arguing with a friend or fleeing from a pack of raccoons.
In those situations, the hypothalamus—which is an almond-size structure in the brain, releases corticotropin-releasing hormone which acts on the pituitary gland, the pea-sized structure sitting just underneath the hypothalamus.
In response, the pituitary gland sends out adrenocorticotropic hormone, or ACTH, which travels through the blood to the zona fasciculata of the adrenal glands and signals cells there to release cortisol.
One of cortisol’s main jobs is to increase blood glucose levels by promoting gluconeogenesis in the liver. This is the formation of glucose from noncarbohydrate sources, like amino acids or free fatty acids.
Cortisol also gets the muscles to break down proteins into amino acids and gets adipose tissues to break down fats into free fatty acids, both of which provide the liver with more raw materials to work with.
The increase in glucose lets the body respond appropriately to those raccoons, or other stressors. Finally, there’s the innermost layer of the adrenal cortex which is the zona reticularis, and cells there make a group of sex hormones called androgens.
This process starts when 17 hydroxypregnenolone and 17 hydroxyprogesterone from the zona fasciculata move into the zona reticularis.
The enzyme 17, 20 lyase turns 17 hydroxypregnenolone into dehydroepiandrosterone and turns 17 hydroxyprogesterone into androstenedione.
Dehydroepiandrosterone can also be turned into androstenedione by the enzyme 3 beta-hydroxysteroid dehydrogenase. Then, androstenedione is turned into testosterone by the enzyme 17 beta hydroxysteroid dehydrogenase.
Alternatively you can also get testosterone by converting dehydroepiandrosterone to androstendiol first with the same enzyme, then using 3 beta hydroxysteroid dehydrogenase to get testosterone.
The adrenal glands are involved in testosterone production in both men and women, but the amount that the adrenals contribute is pretty small in men compared to the testes.
In men testosterone is responsible for the development of male reproductive organs and secondary sex characteristics like voice changes and facial, underarm, and pubic hair.
Since women do not have testes, they have relatively low levels of testosterone, and it’s just enough to influence secondary sex characteristics like underarm and pubic hair.

Pathology5:40–6:36

Congenital adrenal hyperplasia can be caused by a number of enzyme deficiencies in the adrenocortical steroid pathway. These enzyme deficiencies result in low levels of multiple adrenocortical steroids, with cortisol always being one of them.
Low level of cortisol triggers the pituitary to release more ACTH which stimulates the cells in the adrenal gland to continually proliferate.
This results in the enlargement, or hyperplasia, of the adrenal gland. The most common enzyme deficiency is 21 hydroxylase deficiency which is found in both the zona glomerulosa and the zona fasciculata.
In general an enzyme deficiency will cause a build up of the steroid before it in the pathway, and a decrease in the steroid that comes after it.
Without 21 hydroxylase, the adrenal cortex is unable to produce both cortisol and aldosterone. A deficiency in cortisol causes hypoglycemia, and a lack of aldosterone results in loss of sodium and water in the urine and increased potassium in the blood.

21 hydroxylase deficiency6:36–7:14

This is commonly referred to as "salt-wasting." When 17 hydroxyprogesterone and 17 hydroxypregnenolone fail to get used in the cortisol pathways, they get shunted into the zona reticularis and eventually become androgens.
Since women normally have low level of androgens, this increase is enough to cause masculinization of the female genitals and early development of secondary sexual characteristics.

11 beta-hydroxylase deficiency7:14–8:01

The second most common enzyme deficiency in congenital adrenal hyperplasia is 11 beta-hydroxylase deficiency. Similar to 21 hydroxylase deficiency, this condition results in decreased cortisol and aldosterone, and increased androgen production.
However, 11 beta hydroxylase deficiency is distinguished from 21 hydroxylase deficiency by the presence of hypertension, which is caused by the buildup of 11 deoxycorticosterone.
Since 11 deoxycorticosterone is an earlier version of aldosterone, it acts like a weaker version of it, and the large buildup of 11 deoxycorticosterone explains why there’s hypertension despite the low levels of aldosterone.

17 alpha-hydroxylase deficiency8:01–9:26

The third most common enzyme deficiency in congenital adrenal hyperplasia is 17 alpha-hydroxylase deficiency. This enzyme deficiency prevents pregnenolone and progesterone in the aldosterone pathway from being converted into 17 hydroxypregnenolone and 17 hydroxyprogesterone, which is needed in the corticosteroid pathway.
When the levels of 17 hydroxypregnenolone and 17 hydroxyprogesterone are low, they also won’t be able to get into the androgen pathway and become dehydroepiandrosterone and androstenedione.
So this condition results in decreased cortisol and androgens which causes poorly developed genitals and secondary sex characteristics in males, and a lack of secondary sex characteristic in females.
Pregnenolone and progesterone are shunted down the aldosterone pathway, leading to a buildup of 11 deoxycorticosterone as well as corticosterone.
Elevated levels of these weaker versions of aldosterone result in hypernatremia, hypokalemia, and hypertension. Even though the pathway is shunted to the aldosterone pathway the level of aldosterone is surprisingly low.
That’s because the elevated blood pressure, results in low levels of renin, which effectively shuts down the renin-angiotensin-aldosterone system.

Symptoms9:26–10:54

Symptoms of congenital adrenal hyperplasia depends on the enzyme deficiency. In 21 hydroxylase and 11 beta-hydroxylase deficiency, there’s an increase in androgens which causes masculinization of females.
Changes include enlargement of the clitoris, acne, and hirsutism, which is the growth of facial and chest hair, and possibly even ambiguous genitalia.
It could also cause early onset of puberty in females and early appearance of pubic and axillary hair. On the flip side, In 17-alpha hydroxylase deficiency, there are low levels of androgen so males might have ambiguous genitalia and undescended testes, while females might lack of secondary sexual characteristics like pubic and axillary hair.
For the aldosterone pathway, in 21 hydroxylase deficiency there are decreased levels of steroids in the aldosterone pathway which leads to salt wasting, particularly in infants and can cause life-threatening vomiting, dehydration, and hypotension.
In 11 beta-hydroxylase deficiency and 17 alpha-hydroxylase deficiency there’s an increase earlier versions of aldosterone which can cause hypertension.
All three enzyme deficiencies result in low cortisol levels which could lead to hypoglycemia. To help you remember the symptoms for each enzyme deficiency, imagine a family consisting of three siblings: a 21 year old women, representing 21 hydroxylase deficiency, taking care of her 17 year old brother, representing 17-alpha hydroxylase deficiency, and a 11 year old younger sister, representing 11 beta-hydroxylase deficiency.

Diagnosis10:54–11:20

The 21 year old woman is shaving her facial hair representing masculinization. The 11 year old younger sister is watching her and doing the same representing her masculinization as well.
The 17 year old brother has ambiguous genitalia and is not completely comfortable with his male gender identity. The two younger siblings tend to eat a lot of salty snack when their older sister isn’t around which causes hypernatremia and hypertension.
When the older sister finds out, she throws away all their junk food which represents salt wasting. The three of them lives in a happy little stress free suburb which represents low cortisol levels in all three disorders.
Congenital adrenal hyperplasia is normally diagnosed based on symptoms and blood and urine tests that help identify enzyme deficiencies in adrenocortical steroid synthesis pathway.
In many countries, including the United States, 21 hydroxylase deficiency is screened for at birth and will show elevated levels of 17 alpha hydroxyprogesterone if positive.

Treatment11:20–11:45

Treatment of congenital adrenal hyperplasia often involves hormone therapy with cortisol, aldosterone, testosterone, or estrogen depending on what hormones are deficient.
Cortisol in particular helps to suppress ACTH levels via negative feedback, and therefore prevents further hyperplasia of the adrenal glands.
Early surgical correction of genitalis is also sometimes recommended. Ok, quick recap: Congenital adrenal hyperplasia is an overgrowth of the adrenal glands present at birth and is caused by a deficiency of various enzymes in the steroid synthesis pathway of the adrenal cortex.

Review11:45–12:09

The most common type is 21 hydroxylase deficiency, which is usually presents as masculinization in women and salt wasting and hypoglycemia.